Pulmonary fibrosis characterizes a heterogeneous group of lung disorders with irreversible destruction of lung architecture and disruption of gas exchange. The prototype of these diseases, idiopathic pulmonary fibrosis (IPF), has a short median life expectancy from diagnosis to death. Mutations in the genes encoding the protein component (TERT) or RNA component (TERC) of telomerase, a ribonucleoprotein enzyme that catalyzes the addition of hexameric nucleotide repeats to the ends of linear chromosomes, cause disease in a subset of kindreds with familial pulmonary fibrosis. An equal number of families has evidence of telomerase dysfunction, with very short peripheral blood telomere lengths, but no coding mutations in the telomerase genes. Our hypothesis is that short telomere lengths, caused by mutations in genes other than TERT or TERC, represent an important mechanism underlying IPF. In this grant application we merge traditional clinical phenotyping and linkage methods with next generation exome sequencing to provide new insights into IPF genetics. First, we will characterize the clinical phenotype associated with very short telomere lengths in rare kindreds that demonstrate autosomal dominant co-segregation of pulmonary fibrosis and short telomere lengths. Since extreme phenotypes represent a powerful tool for gene discovery, we will use clinical evaluations and analyses of tissue telomerase expression, lung transcriptome signatures and circulating biomarkers to characterize the short telomere IPF phenotype. Second, we will use next generation exome sequencing to identify rare candidate variants in the discovery cohort of kindreds without mutations in known familial pulmonary fibrosis genes. The datasets will be filtered and prioritized by four independent methods: (1) by genomic regions co- segregating with the phenotypes of lung fibrosis and/or short telomere length, (2) by allele frequency, (3) by predicted deleterious effects on protein function and (4) b gene-based frequencies and their biological roles in telomere and fibrosis pathways. The final aim will validate candidate variants by co-segregation in the kindreds they were discovered, by association studies and by investigations of protein variant function. These studies have the potential to break new grounds by determining how telomere shortening leads to lung fibrosis. Our multi-pronged approach offers the promise of new targets for therapeutic intervention and will lead to better understanding of the pathogenesis of progressive lung fibrosis due to telomerase dysfunction.